2-Keto,4-enol-uracil

The aromaticity of the pyrimidine and purine ring systems and the electron-rich nature of their —OH and —NHg substituents endow them with the capacity to undergo keto-enol tautomeric shifts. That is, pyrimidines and purines exist as tautomeric pairs, as shown in Figure 11.6 for uracil. The keto tautomer is called a lactam, whereas the enol form is a lactim. The lactam form vastly predominates at neutral pH. In other words, pA) values for ring nitrogen atoms 1 and 3 in uracil are greater than 8 (the pAl, value for N-3 is 9.5) (Table 11.1). 

Fig. 15.4. Keto/enol and amino/imino tautomeric forms of uracil, cytosine, adenine, guanine. The keto and amino forms predominate, the enol and imino forms are only present in equilibrium at 0.01 Vo or less...

From these observations, it would be predicted that a partial keto-enol tautomerism of the carbonyl groups (last entry in Table III) such as is found in the singly ionized uracil molecule, would lead to a two and a half-fold decrease in reactivity. Hence, the fivefold decrease in e aq reactivity upon ionization of the pyrimidine ring may be accounted for by a twofold decrease because of the negative charge and a two and a half-fold decrease because of the partial tautomerization. 

Table III. Effect of Keto-enol Tautomerism on e aq Reactivity of Uracil...

It is generally believed that among the pyrimidine bases, uracil and thymine mainly exist in the keto form. However, the existence of a small amount of the enol form of these compounds has also been indicated in some experiments. Hauswirth and Daniels have explained the observed deviation in the excitation spectrum of thymine firom the corresponding absorption spectrum in terms of the possibility of emission firom the enol tautomer. On the other hand, Vigny and Duquesne observed that both absorption and fluorescence excitation spectra of thymine are in resemblance with each other. Suwaiyan et al. have suggested the existence of a small amount of the enol tautomer in aqueous solutions of 5-chlorouracil at room temperature. The existence of keto-enol tautomerism in uracil, thymine and their derivatives has also been suggested in supersonic jet-cooled spectroscopic studies. ... 

Three different substituted pyrimidines are found in the nucleic acids, namely cytosine (2-oxy-4-aminopyrimidine) which is present in both DNA and RNA, uracil (2,4-dioxypyrimidine) which is present in RNA but not in DNA and thymine (5-methyluracil) which is present in DNA but not in RNA. They all exhibit keto-enol tautomerism. 

Nudeic acid bases exist as mbctures of two or more rapidty interconvertible isomers of tautomeric forms. Tautomers, at least in prin< le, can be separated at low temperatures where the rate of interconversion is low. The keto-enol equilibrium is the classic example of tautomerism. Hie enol is present in small amount, since it is usually less stable than the keto form. Uracil (1) is one of the nucleic add bases, that exists as mixture of the tautomeric keto and enol forms (Scheme 1). The ratio of the enol tautomer to the keto tautomer of uradl, however, is small. The existence of the enol form of Sdieme 1 is the basis for referring to uracil as dihydroitypyrimidine. 

Other pyrimidine keto-nucleosides, such as 47a and 47b, could be treated with acetic anhydride-pyridine without glycosylic cleavage.33 The stability of 47a and 47b in this medium permitted elaboration of a new, mild, regioselective synthesis of enol acetates, The reaction of 4 -ketonucleosides of uracil with acetals of N,N-dimethylformamide led,33 after addition of acetic anhydride, to the corresponding enol acetate-nucleosides 77a and 77b. 

All pyrimidines and purines can exist in alternative isomeric forms called tautomers. Thus, uracil can exist in keto and enol forms. 

All pyrimidines and purines can exist in alternative isomeric forms called tautomers. Thus, uracil (Fig. 3-29), thymine (Fig. 3-29), and guanine (Fig. 3-31) and can exist in keto and enol forms (Fig. 3-32). The keto form dominates at neutral pH. 

A useful method for preparing enol-acetates from uracil 4-keto-nucleosides uses dimethyl formamide diethyl acetal followed by acetic anhydride 2-keto isomers, or N-3-substituted analogues, did not react. Further studies supported a mechanism involving 0-4 esterification of the nucleoside followed by enoliza-tion, which is intramolecularly catalysed by the dimethylamino group, as illustrated in (63). 

Marked changes occurred in the infrared spectra when polyuridylic acid and polyadenylic acid were mixed, and the changes were considered to result from hydrogen-bonding interaction between them. These quantitative measurements supported the conclusion that infrared spectra of such mixtures provide experimental evidence that the uracil units are present in the keto form and that the adenine units are probably present in the amino form, as in the Watson-Crick DNA model. Earlier it had been demonstrated (Miles, 1956 1958o) by means of infrared spectra of appropriate model compounds that the band at 1692 cm is characteristic of the keto form of uridine and would be absent in the enol form. It had also been shown that the 1630 cm band is probably indicative of the amino form of adenosine. If interaction of the polymers involved the enol form of uridine, there would be no band at 1695 cm in the mixture. 

The RNA base uracil is a pyrimidine derivative, usually depicted in its keto form (page 396). The enol tautomer readily undergoes electrophilic substitution, unlike most pyrimidines. 

Nucleic acids (DNA and RNA) contain substituted purines and substituted pyrimidines (Section 26.1) DNA contains adenine, guanine, cytosine, and thymine (abbreviated A, G, C, and T) RNA contains adenine, guanine, cytosine, and uracil (A, G, C, and U). Why DNA contains T instead of U is explained in Section 26.10. Unsubstituted purine and pyrimidine are not found in nature. Guanine (a hydroxypurine) and cytosine, uracil, and thymine (hydroxypyrimidines) are more stable in the keto form than in the enol form, so the keto forms are shown here. We will see that the preference for the keto form is crucial for proper base pairing in DNA (Section 26.3). 

Thymine and uracil exist only in the keto-tautomer both in the gas phase and in solution [132-138]. Thus, very recent QCISD(T)/6-31 l-FG(d,p) calculations show that the di-keto tautomers of uracil and thymine were preferred by more than 10 kcal/mol over the enol-keto ones in the gas phase [132]. Such a preference remains nearly unaltered in aqueous solution, as suggested from the results of MC-FEP and ab initio SCRF [132] calculations. 

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